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I . INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
I 1 . FUNCTIONAL G R O U P INTERCONVERSION OF CARBOXYLIC
ACID DERIVATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
A . Formation of Alcohols and Ethers . . . . . . . . . . . . . . . . . . . . . 617
B. Formation of Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
C . Formation of Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
D . Formation of Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
E. Formation of Nitriles and Isonitriles . . . . . . . . . . . . . . . . . . . . 624
F. Decarboxylations and Decarbonylations . . . . . . . . . . . . . . . . . . 625
1. Replacement by hydrogen (RCOX + RH) . . . . . . . . . . . . . . . 625
2. Formation of alkenes [C(X)-C(C0Y) + C=C . . . . . . . . . . . . 628
G . Interconversion Between Carboxylic Acid Derivatives . . . . . . . . . . 629
I11 . a-FUNCTIONALIZATION OF CARBOXYLIC ACIDS
A N D THEIR DERIVATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . 631
IV . CARBON-CARBON BOND FORMATION USING CARBOXYLIC
ACIDS A N D THEIR DERIVATIVES . . . . . . . . . . . . . . . . . . . . . 635
A . Carbon-Carbon Bond Formation at the Carbonyl Group . . . . . . . 635
1. Acylation reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
2. Reactions of acid derivatives with organometallic reagents . . . . . . 641
3 . Acyloin reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
4 . Miscellaneous reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 645
B. Carbon-Carbon Bond Formation x to the Carbonyl Group . . . . . . 647
1 . Alkylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
2. Acid derivative condensations with aldehydes and ketones . . . . . . 652
3. Acid derivative condensations with acid derivatives . . . . . . . . . . 658
4 . Radical- and carbene-mediated cyclizations . . . . . . . . . . . . . . . 660
5. Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
C. Carbon-Carbon Bond Formation at Remote Positions . . . . . . . . . 666
1. a-Bond formation by Michael reaction . . . . . . . . . . . . . . . . . 666
2. P-Bond formation by other reactions . . . . . . . . . . . . . . . . . . 669
3. Positionallv more remote bond-formation reactions . . . . . . . . . . 671
Supplemenl B : The Chemistry of Acid Derivatives. Vol . 2
Edited by S . Patai 0 1992 John Wiley & Sons Ltd
615
616 Jeffrey Hoyle
1. INTRODUCTION
The synthesis of complex, polyfunctional organic molecules, in a stereocontrolled
manner, is surely one of the wonders of modern chemistry. The beauty and elegance
of the methodologies devised and reported in the literature, especially by the world’s
major synthetic groups, often leaves one totally spellbound upon first reading.
A cursory glance at almost any modern synthetic sequence will convince the reader
of the central importance of carboxylic acid derivatives as sources of chiral starting
materials, as key intermediates and as target molecules. The reader is referred to the
excellent Art in Organic Synthesis by Arnand, Bindra and Ranganathan’ which
chronicles key syntheses that have been successfully completed over the last few decades.
This work amply indicates the central role of acid derivatives in synthetic organic
chemistry.
An excellent review2 on the synthesis of natural pheromones has shown the impor-
tance of naturally occurring, optically active, carboxylic starting materials such as
a-amino acids, tartaric and citronellic acid. The review has also shown the importance
of acid-derived functional group interconversions, of lactonization as a key synthetic
step, of fractional crystallization of acidshases for enantiomeric separation and of the
many carbonxarbon bond-forming reactions which are possible with acid derivatives.
Many other workers have espoused the use of other acid derivatives as synthetic
substrates, such as glutamic acid3 and sugar lactones4, and have extolled the virtues of
carboxylic acid derivatives in all aspects of synthetic chemistry.
Thus, carboxylic acids and their derivatives are probably the most versatile tools
available to the synthetic organic chemist. Conversions to amines, aldehydes, alcohols,
ethers, halides and hydrocarbons may be readily performed. In some cases a carbon
atom is lost giving ‘nor functionalities’. In addition, interconversion between the different
acid derivatives is easy to achieve. a-Functionalization of carboxylic acid derivatives
may also be performed readily as may decarboxylation and decarbonylation. However,
the major synthetic importance of acids and their derivatives arises from the ease by
which they may be used in carbonxarbon bond-forming reactions and in the prepara-
tion of heterocycles.
In this review all the above-mentioned, useful synthetic processes will be discussed in
detail with examples taken mainlv from the chemical literature since 1980.
The present work does not cover the use of acyl silanes in synthesis and the reader
is referred to the reviews of Age?, Bullman Page and coworkers6 and Ricci and
11. Synthetic uses of carboxylic acids 617
r
RCH,OH
ROH
I1
R-C-Y
T RCH,OR‘
alkenes RCHO
RH RX
RCH, X = F,CI,Br,I
618 Jeffrey Hoyle
Reaction of carboxylic acids using mild conditions with lithium aluminium hydride
produces primary alcohols, via aldehydes which are themselves difficult to isolate in
many instances (however, see Section 1I.B). Sodium borohydride may also be employed
if used in combination with activators such as N,N-dimethylchloromethyleniminium
chloride". In this case, reduction of the acid group may be performed selectively in the
presence of other reducible groups such as esters, halides, olefins and nitriles (equation
2)23. The carboxylic acid group in an N-protected a-amino acid was reduced to an
alcohol, at O"C, by use of borane in THFZ4.Catalytic hydrogenation at low temperatures
and pressures, with a ruthenium catalyst, has also been used to prepare alcohols from
carboxylic acids".
CI -
CI-NMe,=CHCI NaBH
RCOz H RCOOC=&Me, 4 RCH,OH (2)
I
H
RoxzEt
Lithium aluminium hydride (LAH) and lithium borohydride reduction of ortho esters
gives an allylic alcohol as major product with, in most cases, a small amount of the
Rod LIAIH,, OH
(4)
11. Synthetic uses of carboxylic acids 619
expected trio1 (equation 7)42. The allylic alcohol has been shown to be formed by
reduction of a decarboxylated intermediate.
/Co2R'
R-C-C02R'
\
C0,R'
- RC
/CH20H
\
CH2
+ FH20H
R-C-CH,OH
\
CH,OH
(7)
major minor
CH3(CH2)3
H
\
FC\
/
H
(CHWO2Me
-I. LAH,A
2. CH,COCI
CH3(CH2)3
\
/c=c\
H
/
H
(CH,),,CH,OCCH,
n = 3, 5, 7 , 8 , 9
(8)
R I R I
Ar Ar
triarylfuranones (lactones) are also reduced to the ether level by the use of dimethyl
sulphide-borane complex, as exemplified in equation lo4'.
Attempts to produce cyclopropane carboxaldehydes by reduction of the correspond-
ing esters have resulted in ring-expanded ethers as shown in equation 1 I 3 O .
Thiol esters (RCOSR') are converted to sulphides with Raney nickel whilst thiono
esters (RCSOR') produce ethers with the same reagent4'.
Acyl halides are reduced to primary alcohols by LAH. Other hydride transfer reagents,
such as NaBH,, may also be employed50.
Chain shortening of acyl halides leads to excellent yields of nor-alcohols via a radical
-
chain reaction in the presence of dimethyl sulphide (equation 12)5'.
Me$
RCH,COX [RCH,OOH] RCH,OH (12)
LAH reduction of anhydrides also produces alcohols. With cyclic anhydrides, either
diols or lactones are formed depending upon the reaction conditions. In the first
laboratory synthesis of the first lignans to be found in humans, and animals, an anhydride
was identified as the key intermediate. Upon reduction with sodium borohydride in
DMF the anhydride yielded one lignan (a lactone) as shown in equation 13 whilst
reduction with LAH afforded another lignan (a diol) as shown in equation 1452.
Hov HOCH,
CH,OH
(14)
B. Formation of Aldehydes
While reduction of carboxylic acid derivatives usually leads to primary alcohols as
the major products, the methodology for halting the reduction at the aldehyde stage is
also well established and this has been reviewed recently by Cha53.
Carboxylic acids may be reduced to aldehydes, via imines, by reaction with lithium
in either ammonia o r a simple primary amine, followed by hydrolysis.
11. Synthetic uses of carboxylic acids 62 1
The use of boron-containing reagents for the conversion of carboxylic acids, and their
- ~ ’ . and lithium salts of
salts, into aldehydes has received much a t t e n t i ~ n ~ ~ Sodium
acid^^^.^^, and acids t h e m s e l ~ e s ~react ~ , two equivalents of thexylborane-di-
~ * ~ with
methyl sulphide complex to give extremely high yields of aldehydes at room temperature
(equation 15). A similar reaction also takes place if 9-borabicycloC3.3. llnonane (9-BBN)
is used as reducing agent58*69.
RCHO
Complex aluminium hydrides in pyridine with N,N-dimethylchloromethyleniminium
chloride6’ or in refluxing THF63 also produce excellent yields of aldehydes. Aldehydes
may also be formed by reaction of an acid with a Grignard reagent with a titanium-
containing catalyst followed by h y d r ~ l y s i s ~ ~ .
Esters may be readily reduced to aldehydes by use of either diaminoaluminium hydride
or by diisobutylaluminium hydride at low temperatures (equation 16)65. For example,
the protected methyl 3,5-dihydroxy-l-cyclohexaneacetate was reduced to the aldehyde
en route to 2,4-dioxaadamantane, as shown in the equation. A patent has been filed for
the hydrogenation of esters to aldehydes using either yttrium or zirconium oxides as
catalyP.
/CO,Me /CHO
HAI(i-Bu),
- 78°C
@ = TBDMSft-BuMe,Si-)
Acid chlorides have been reduced to aldehydes using LiAIH(OBu-t), at - 7 8 v 7 ,
with tributyltin h ~ d r i d e ~by~ catalytic
. ~ ~ , hydrogenation (Rosenmund
by chromium or tungsten hydrides7’ and with both sodium and complex copper
borohydrides in a polar aprotic ~ o l v e n t ~ The~ - ~latter
~ . reaction may be catalysed by
metal ions, in which case non-acyl halides present in the molecule being reduced are
unaffected7’. Polymer-supported hydrides have also been used to prepare aldehydes by
reduction of acyl ~ h l o r i d e s ~ ~ * ’ ~ .
Nor-aldehydes are produced from acyl chlorides via a radical reaction involving
-
treatment with TsCl in pyridine (equation 17)5’.
TsCl
RCH,COCI RCH,OOH pv RCHO (17)
In a synthetically very useful reaction, acyl halides have been converted into nor-
aldehydes by initial conversion into acylcobalt salophens followed by sunlamp irradia-
tion with nitrogen monoxide, in dichloromethane, and hydrolytic work-up, as shown in
equation 18s0~8*.
Disubstituted amides may be reduced to the aldehyde level by the use of lithium
622 Jeffrey Hoyle
I . h,NO
RCH,COCI ----+ RCH'CO-Co(sa1ophen) RCHO (18)
aluminium hydride although it is very difficult to stop the reaction at this stage. Alcohols
are nearly always produced as by-products and this reaction has been reviewed
previously in an earlier volume of the present series6'.
A special group of amides, Reissert compounds, may easily be converted into
aldehydes simply by treatment with sulphuric acid, as shown in equation 19"'. (Reissert
compounds are produced by reaction of a carboxylic acid with quinoline and cyanide
ion.)
ArCONHPh *, PCI,
1.
H30+* ArCHO
C. Formation of Amlnes
The formations of amines from carboxylic acid derivatives include the classical Curtius
and Schmidt reactions and the Hofmann rearrangement and the hydride reduction of
amides.
In the Schmidt reaction the acid is reacted with hydrazoic acid to give an intermediate
isocyanate, which upon hydrolysis yields the amine as shown in equation 21a4. A similar
functional group transformation may be performed in 51-86% yield, in a single pot, by
reaction of aromatic or heteroaromatic acids with thionyl chloride followed by hydroxy-
lamine-0-sulphonic acid in dry toluene under refluxe5.
Hofmann rearrangement of unsubstituted amides gives amines, again via the isocya-
natea6-88. The intermediate may be isolated if the reaction is performed under phase-
transfer conditionse9. Similarly, the Curtius rearrangement of acyl azides and the Lossen
rearrangement of RCONHOCOR also produce amines via the isocyanate upon hydro-
l y ~ i s " " - Using
~ ~ . the Hofmann rearrangement, N-protected 2,3- and 2,4-diaminobutyric
acids, needed for solid-phase peptide synthesis, have been prepared from N-protected
asparagine and glutamine, respectivelya6.
In general, the reduction of a wide structural variety of amides with hydride transfer
reagents3', b ~ r a n e ~ l or
. ~ by
' catalytic hydrogenation also produces amines (note the
exception of disubstituted amides with LiAIH, as discussed in Section 1I.B). In this
11. Synthetic uses of carboxylic acids 623
0 0
1I I , Zn/HOAc/Ac,O II
, RCCH NH
RCCN 2. HC1.A
D. Forrnatlon of Halides
There are very few ways to prepare a halide from an acid in good yields. The classical
Hunsdiecker method is one well-used exception although some others of limited
applicability are also available, and will be discussed.
Halides with one carbon atom fewer than the starting acid may be formed by the
Hunsdiecker reaction of bromine with silver salts of carboxylic acids. Except where the
acid is unsaturated, the reaction is of widespread applicability. In a short, stereoselective
synthesis of a sex pheromone of the citrus mealybug, Hanococcus citri (Risso), ( + )-cis
pinonic acid [prepared by oxidation of ( +)-a-pinene] was halodecarboxylated using the
Cristol-Firth variation of the Hunsdiecker reaction (equation 25)97.In more recent years,
thallium salts have been employed since these are more readily prepared and much more
easily purified than the silver salts9'. A radical reaction, involving organoantimony
compounds, has been used to form nor alkyl iodides from acids2'.
Alkyl fluorides have been produced, in 5 4 8 4 % yield, by treating acids with xenon
fluoride and H F (equation 26)99. This method was unsuccessful in the presence of
hydroxyl groups and so could not be used for the fluorodecarboxylation of cholic acid.
If acyl halides, with no a-H atoms, are heated with either Wilkinson's catalyst
[RhC1(Ph,),]lOO*lO1 or palladiumlo2, then alkyl halides are formed in reasonable yields.
Alkyl halides (CI, Br, I) are also obtainable from acyl halides by treatment with iodoform,
with amine catalysis103.
Arylmethyl acyl halides have been used to prepare arylmethyl halides via cobalt
salophens by irradiation in the presence of bromotrichloromethane". This react ion
624 Jeffrey Hoyle
X = I, Br
CO~NH, CN
R = H, CH,
11. Synthetic uses of carboxylic acids 625
Both amides and thioamides may be used to prepare nitriles under phase-transfer
conditions in yields in excess of 60%'l3, whilst thioamides are converted into nitriles
by reaction with 2,4-dichloro-5-nitropyrimidine1 14.
Formamides may be converted into isonitriles by reaction with trifluoromethane-
sulphonic acid at -78"C, in high yield, as exemplified in equation 29'". The formamide
may be conjugated to an olefin and such a reaction has been employed for the
preparation of isonitrin B, a metabolite produced by fungi of the genus Trichodvrrna
(equation 30)''6*11 7 .
+OSiMe,Bu-t
I
NC
Bu,NF, THF
0 GH NC
PLE , I . (COCI),
I
0-
3. r-BUSH. A
Z = C0,Me
Malonic esters and /I-ketoesters are readily decarboxylated by initial transesterifica-
tion to the corresponding acid, catalysed by onium ions (equation 35)134and by many
other methods. The extremely important synthetic aspects of these reactions have been
reviewed by K rapcho12s . L 2 6 .
Palmitic acid has been converted into pentadecane, in 85% yield, by treatment of an
organoantimony compound, formed via a radical reaction, with oxygen-free HC12*.
11. Synthetic uses of carboxylic acids 627
R'
n-C,,H,,C02H,
cat, A RXH
X
R'
(35)
H-abstraction
RH
C0,Et C0,Et
<Co2Et I . base
A tC0,Et 1. base RfC0,Et LDA R<Co2Et
2. CIC0,Et
C0,Et
CO2Et C0,Et C0,Et
(39)
decarboxylation process serves as a means by which controlled mono alkylation may
be performed in malonic acid synthesis, as exemplified by equation 39.
Primary or secondary acyl halides produce good yields of hydrocarbons, by dehalo-
carbonylation, upon heating with tripropylsilane in the presence of t - b u t y l p e r ~ x i d e ' ~ ~ .
I I
-c-c- PMOAc),, \
I I
H C0,H
& CO,CH,CH=CH,
P4OAc)z)
I . ?-his(diphenyl-
phosphinokthane
/j-Hydroxyacids may be converted into alkenes under very mild conditions using
diethyl azodicarboxylate (equation 43)'45. The same reaction also occurs for p-lactams,
presumably via the /]-amino a ~ i d ' ~ ' . ' ~ ' .
Other reagents may also be used for this c o n ~ e r s i o n.'sI' ~ ~For
~ example, /I-hydroxy-
acids are converted stereospecifically into alkenes by catalysis with tungsten tetra-
chloride in basic acetonitrile (equation 44)"'.
EtOzCN=NCOzEt
(43)
OH 0,
C4
' 0 C . Ph,P
I
OR
1 1 . Synthetic uses of carboxylic acids 629
R' R"'
Esters with P-H atoms undergo thermal elimination producing a carboxylic acid and
an alkene (equation 45). This reaction is usually performed in the gas phase. By this
method, allylic acetates have been usefully converted into dienesI5'.
LIBH,
- C0,Me J
1
PLE
C
' OZH
COZBU-t COzH
RNH,
I + RCONHR"
Dehydration of acids with phosphorus pentoxide and other reagent gives anhy-
d r i d e ~ ~ ~ * which
''', may also be produced by reaction of carboxylates with acyl halides
under phase-transfer conditions'". In the latter case unsymmetrical anhydrides may be
prepared, whilst the former case is generally only useful for symmetrical anhydrides.
Both cyclic and acyclic anhydrides may be formed in many different ways by dehydration
of carboxylic acids. One modern method involves the use of trimethylsilylethoxy-
acetylene in an inert ~olvent''~.
Thiolesters are the most easily prepared from acid derivatives by treatment of acyl
halides with thiols, or by successive treatment of an ester with LDA, chlorotrimethyl-
silane and hydrogen ~ulphide"~.Thioacids may be prepared by reaction of esters, acyl
halides or anhydrides with hydrogen sulphide'" and thiolactams may be synthesized
from lactams by treatment with phosphorus pentasulphide' 92.
RCH2C02H + X, + RCHC0,H
I
X
632 Jeffrey Hoyle
Iodine may be introduced by using a modification of the above procedure using iodine
with chorosulphonic acid as the catalyst195s196,or by refluxing a carboxylic acid with
iodine and a copper salt197.
a-Halogenation may also be performed by reaction of an acid derivative with a base
followed by a source of positive halogen such as N-halosuccinimides. In one such
method, fluorine has been successfully introduced by reaction of acids with LDA
followed by acetyl hypofluorite (CH3COOF)198.
a-Haloesters may be prepared by a-halogenation of an acid, followed by esterifica-
tion 193.199. a-Bromoesters may also be prepared by reaction of malonic ester analogues
with bromine, initiated by irradiation with a mercury lampzo0.
a-Haloesters are very useful in synthesis, for example, in the Reformatsky reaction and
the Darzens condensation (Section IV), in the preparation of 0-silyl ketene a ~ e t a l s ’ ~ ~ ,
in the preparation of acyliminoesters (which are used to prepare unnatural a-amino acid
derivatives, equation 5 1)’01, in a novel stereocontrolled, electrochemical synthesis of
~-lactamszoz, in the Blaise reaction (equation 52)’03 and in the Arbuzov reaction where
a phosphonoacetate group is produced (equation 53)’04. These organophosphorus
compounds may be used to form a-alkylated acrylate esters by reaction with for-
maldehyde.
Br
I
RCHC0,R’ ‘E10)3Ph (EtO),PO-CHC0,R’ (53)
I
R
a-Bromolactones, derived from L-ascorbic acid, have been prepared from the corre-
sponding hydroxy compounds as depicted in equation 54205-207.Such compounds are
OH
OH
I /OH I
CH, /OH
CH,-CH HBr ‘CH
(54)
AcO Br
1 1. Synthetic uses of carboxylic acids 633
easily purified and characterized and have been used for the synthesis of some novel
furanone chirons (i.e., chiral synthons), useful in natural product synthesiszo7.
a-Haloamides may be synthesized by reaction of a-anions of amides with electrophilic
halogen sources. These products are useful in a variety of synthetic sequences and have
been used in base-induced reactions which give a series of linear and cyclic polyfunctional
products”’.
Both primary and secondary a-bromoamides react with a range of a-aminoacids to
form esters in the presence of silver oxide, in acetonitrile, as shown in equation 55”’.
The chiral centre in the a-bromoamide remains unchanged whilst the chiral centre from
the amino acid is epimerized.
No,
8-Hydroxy-*-amino acids may be prepared by reaction of 2,3-epoxyacids with
diethylamine in the presence of tetraisopropoxytitanium211.z1z . Thi s reaction also occurs
with the corresponding amides” I . Both mono- and disubstituted a-amino malonates
have been prepared by insertion of bis(methoxycarbony1)arbene into the N-H bond
of a primary or secondary amine, in the presence of copper(I1) acetylacetonate (equation
57)213.
with tosyl azide, and other azides, under phase-transfer conditions as depicted in
equation 59’”. Such diazotized compounds may then be used in carbon<arbon
bond-forming reactions, using carbene methodology. For example, such compounds
with a silyl e n d ether2I9 give a cyclopropane (equation 60) which may be converted
into a wide range of 4-oxoalkanoic acid derivatives by ring-opening reactions. A similar
reaction occurs, albeit in lower yield, if the silyl enol ether is replaced by an alkene2”.
vph
a-Sulphenylation of esters is an important reaction that has been reviewed by
a-Thio groups may be introduced into esters and lactones by reaction with a base
-
followed by a disulphide (equation 62)’’,.
=o I . LPh,S,
2. DA
1. Acylation reactions
Acylations involve carbonxarbon bond formation at the carbonyl group of an acid
derivative and occur at both aliphatic and aromatic carbon atoms. The formation, from
acyl halides with silver salts or Lewis acids and amides by deamination, and reactions
of acylium ions, has recently been reviewedzz9. Jn aromatic acylations, a Lewis acid
catalyst is usually required. Cyclizations, involving C-C bond formation between the
carbon atom of a carbonyl group and an aromatic carbon atom, are considered as
aromatic acylations in the present work. Reactions of a-anions of acid derivatives with
other carboxylic acid derivatives could be considered as acylations o r as C-C bond
formation at the z-position. In this review the latter approach will be used (see Section
1V.B).
Aromatic acylations are historically important in the formation of aromatic ketones.
The most common reaction is the Friedel-Crafts acylation of an aromatic compound
with an acyl halide in the presence of a Lewis acid catalyst (equation 64). For example,
thiophenes and 2-acylthiophenes have been acylated with long-chain acyl halides to give
2-acyl- or 2,5-diacylthiophenes, respectively230. These products were then desulphurized
and unsaturated; long-chain fatty acids and alcohols, with 2&32 carbon atoms, were
produced. The FriedelLCrafts reaction is of very wide scope, is usually prevented by the
presence of electron-withdrawing groups and has been reviewed by MarchZ3l.The ;icy1
halide may be replaced by acids or anhydrides; however, it should be noted that the
use of esters usually produces Friedel-Crafts alkylation.
A related reaction is the Fries rearrangement, where an aryl ester is heated with a
Lewis acid to give either orrho- or para-phenolic ketones. For example, para-crcsol
636 Jeffrey Hoyle
Me Me Me
The high temperatures required for Fries rearrangement often cause alkyl groups to
either migrate or be eliminated. This problem has been overcome, in one instance, by
using titanium tetrachloride in place of AICI, as the catalyst233.A reaction similar to
the Fries rearrangement has also been carried out involving promotion of the process
by ortho-lithiation as shown in equation 66234.
R' R'
k R
R' = H, CH,
R = H, CH,, OCH,,CI
COCF,
Pyrazoles have been directly acylated with oxalyl chloride which, following de-
carbonylation, gave a pyrazole acid chloride (equation 69)239.
r COCOCIi COCl
Q-
- N C
Q
O
f-R N
I H
Z~CI
3-Acylindoles may also be prepared by Friedel-Crafts acylation of N-protected indoles
(a rather lengthy procedure)241and by reaction of acyl halides by the requisite Grignard
reagent (which tends to give diacylation and low yields). These and other methods have
been reviewed242.
Aromatic 2-acylmethylidene-3-methylthiazolines,compounds that possess anti-
inflammatory and analgesic properties, may be synthesized in one-pot by acylation of
thiazolium salts by activated carboxylic acids (equation 71)243,
RCOX + -<z,
Z
- R C O X Z
z (74)
R 8,-I
R k,.I
+ (CH,CO),O ---+
b
Similar acylations occur with a-carbanions formed from a variety of compounds
including nitriles, sulphoxides and sulphones. For example, imides react with the anion
of dimethyl sulphone to give w-amido-8-ketosulphones, which are useful synthetic
intermediateszs3.The sulphur functionalities may be later usefully removed by reductive
desulphurization. Dianions, for example of ketones, react at the least acidic site in the
first instance. Thus, with two equivalents of ester, 1,3,5-triketones may be produced.
Acylation of 1-alkoxy-1-siloxycyclopropanes yields ring-opened y-ketoesters with
various catalysts (equation 78)254.
$:: - R’COCI
0
II
R’CCHzCH2COzR (78)
Acylation of alkenes and alkynes is a very important means by which new C-C
bonds are formed. These reactions have recently been reviewed229.
Trisubstituted alkenes react with alkyl acylium salts to give a$-unsaturated ketones
in reasonable yieldszss, whilst butadiene may be stereoselectively acylated to produce
trans ketone^^^^.^^' . However, in the presence of acetic anhydride, this latter reaction
produces unsaturated ketone acetates as shown in equation 7gZs8.
/
- -Rev[ Rcw
RCOX +
OAc
(79)
OAc
Alkenes react with CH,CO+BF,- in acetonitrile to give, unexpectedly, oxazines
(equation 80) via a c y l a t i ~ n2-Methylpropene
~ ~ ~ ~ ~ ~ ~ . has been converted, regioselectively,
into 1,3,6,8-tetraalkyl-2,7-naphthyridinesby reaction with 4 equivalents of an acylium
salt, followed by treatment with liquid ammonia in a one-pot process (equation
8 1)26‘-263.
640 Jeffrey Hoyle
)=zmRqlR I . 4RCO‘X-
R R
Vinyl silanes react with a,/?-unsaturated acyl halides, in the presence of tin(1V) chloride,
to give bicyclic ketones upon acidic work-up (equation 82)264. This methodology has
been used in the synthesis of naturally occurring k e t ~ f u r a n s ~ ~ ~ .
2. H,Ot
COCl TMS
Allylic halides are acylated by acyl halides, in the presence of aluminium chloride, to
givc overall addition to the double bond (equation 83)266.The products were used to
produce synthetically useful, 1,Cdicarbonyl compounds in several more steps.
Alkenynes complexed to transition metals react with acylium salts at the alkene site.
Good yields of alkynyl ketones are produced by this process, in the presence of
nucleophiles (equation 84)267.268.
CH3 0
1. complexation I II
2, R C O + X ~ ’ HC-C-C-CH,--C-R
//CH2
HCECC (84)
\
CH, N NU- I
Nu
Acyl halides react with trimethylsilylalkynes, with aluminium trichloride catalysis, to
give acylation as shown in equation 85. If the acyl chloride possesses a,@-disubstitution
and it is p,y-unsaturated, then cyclopentenones are formed and a rather surprising, but
useful, synthetic route to spiro[4.4]-nona-2,6-dienones is produced as exemplified in
equation 86269.
0
II
aR
AICI,
RCOCl + R’CECSiMe, RCC-CR’
SiMe,
+ RC-CSiMe,
AlCI,
0
a,/?-Unsaturated acyl chlorides react with alkynes, with Lewis acid catalysis, to give
chlorocyclopent-2-enonesas shown in equation 87’”. Further processing, with silver
11. Synthetic uses of carboxylic acids 64 1
perchlorate and triethylamine, to remove the halogen from the product was used in
order to create an exocyclic double bond. This compound was then used to prepare the
antibiotic methylenomycin B in 47% yield270.
'R
-
phosphorane, to give ketones (equation 88)271*272.
In the synthesis of Prelog-Djerassi lactone, Hacini and Santelli have reacted (-)-
trans-pulegenic acid with methyllithium to give the methyl ketone in a highly stcreo-
controlled fashion as shown in equation 89273.
Lithium formate reacts with Grignard reagents to give aldehydes in excellent yields.
Reduction and halogenation completes a neat overall homologation of the original alkyl
halide from which the Grignard reagent was preparedz74. Lithium carboxylates react
with organolithium compounds to give ketones, upon aqueous ~ o r k - u p ~ ' ~ . ~ ' ~ .
In most instances, esters react with Grignard reagents to give tertiary alcohols whilst
thioesters react with lithium dialkylcopper reagents to give good yields of ketone^^^^.^^'.
2-Pyridyl esters, which may contain bromo, ester and keto functionalities, react with
lithium dialkylcuprates, at - 78"C, to give very high yields of ketones (equation 90)277.
'
This and other reactions of 2-pyridylesters have been reviewed279.
0
RCO + R,'CuLi RCR'
II
CeCI,
RCozMe TMSCH,MgCI ' TMS -TMSOH R
R
OH
Stereocontrolled C-C bond-forming ring closure of a lactone has been performed
by reaction of an ester with an internal Grignard reagent, formed at the a-position to
the carbonyl group of the eventual lactone (equation 92)285.
y-Lactones also react with Grignard reagents to give 1,4-diols upon acid work-up
(equation 93)286.
0 RMg'b L O H (93)
OH
Phthalides react with I,l-dibromoalkanes to give enol ethers, in the presence of zinc
metal and titanium tetrachloride, in T H F with TMEDA (equation 94). This reaction
"'m R'q
has been shown to proceed via organotitanium speciesz8'. The products are benzylidene
phthalans, which under acid catalysis are equilibrated to give isobenzofurans (equation
95); these are useful as dienes in Diels-Alder reactions.
+ RCHBr, 2
TiCl
(94)
Zn
R' R'
0 R
H
R
RC0,R' + Me,SiCH,Br Zn (96)
R'O SiMe,
11. Synthetic uses of carboxylic acids 643
- -
solution (equation 98)292.
R’OH
RC02R’ RCECOLi RCH,CO,R’ (98)
H
Grignard reagents react with dialkyl oxalates to give a-ketoesters at -80°C and this
methodology has been utilized for the preparation of esters of 2-0x0-3-alkenoic acids.
These esters are key intermediates in some synthetic routes to c e p h a l o ~ p o r i n s This
~~~.
method is advantageous over those previously reported since it is a simple, one-pot,
reproducible procedure that uses commercially available materials.
Acyl halides react under mild conditions with a wide variety of lithium dialkylcopper
reagents to give excellent yields of ketones (equation 99). If oxygen is not excluded then
esters are also produced, which in some cases are the major products. This reaction has
been much used in the synthesis of natural p r o d u ~ t s ~The ~ ~acyl
. ~ halide
~ ~ . used may
have a wide range of structures and may contain such functional groups as esters, iodides,
ketones, nitriles and nitro groups.
products are synthetically very important since they are easily transformed into homo-
enolate derivatives.
CI
The reaction of most amides with Grignard reagents gives low yields of a mixture of
ketones, alcohols and amines. However, disubstituted formamides react cleanly with
Grignard reagents to give tertiary amines as depicted in equation 101306, which is known
as the Bouveault reaction.
-
644 Jeffrey Hoyle
n = 3,4, $ 6
-
shown in equation 1033'1.
3. Acyloin reaction
The acyloin reaction of carboxylic acid esters is especially useful for the preparation
of large carbocyclic ring systems.
Esters heated in xylene with sodium undergo the acyloin reaction-a dimerization
involving C-C bond formation to produce an a-hydroxyketone (also known as an
acyloin) as shown in equation lM312.If the two esters are part of the same molecule
then a cyclic product is formed by intramolecular reaction, which has been used to
obtain 10- to 20-membered rings in yields in excess of 60%. This reaction is one of the
best methods of preparing such ring systems. Synthetic genius combined with the acyloin
reaction has been used to prepare both a 34-membered ring and a catenane with two
interlocking 34-membered rings3'*. Much improved yields of acyloins have been
obtained by use of a potassium-graphite intercalation compound (C,K) in the place of
sodium metal3I3.
2RC0,R' 7
Na
RC=CR
I I
NaO ONa
I
1H.O
RCH-C-R
I II
OH 0
Acyloins are also formed under milder conditions if the above reaction is carried out
in the presence of trimethylchlorosilane. Indeed some acyloins may only be prepared
by this latter method (for example ethyl acetate + acetoin). This modified method has
also been used for the preparation of seven-membered heterocyclic compounds as shown
in equation 105314. Use of ultrasonic irradiation improves the yield of acyloins in the
modified reaction and also makes the preparation easier3 '.
1 I . Synthetic uses of carboxylic acids 645
\
C0,Et
I . Me,SiCI/Na
j C 0 , E t 2.H30' '
X
X = S,NR
In a reaction related to the acyloin reaction, ketoesters have been reduced by 1,AH
to give good yields of cyclic ketones via a radical process involving titanium trichloride,
after hydrolysis (equation 106)316.
4. Miscellaneous reactions
There are several miscellaneous C-C bond-forming reactions which occur at the
carbonyl group of acid derivatives that do not fit into the other sub-divisions. It should
be noted that acyl radical cyclizations involving selenoacids are not covered here. The
reader is referred to a recent paper by Crich and coworkers (and references therein) for
details of this type of carbon-carbon bond-forming reaction3 17.
Wurtz-type coupling of acyl chlorides in the presence of pyrophoric lead, lithium or
samarium iodide yields a-diketones (equation 107)318.319.Ultrasonic irradiation allows
the reaction to be performed under milder conditions and gives higher yields319.
Attempted Reformatsky reactions with 2-iodomethyl-2-propenoates have been un-
-
successful, but these substrates undergo Wurtz-type coupling very readily320*32'.
Sml,
2RCOCl RCOCOR (107)
-
equation 108323.
I I I
2ArCC0,H Ar-C-C-Ar (108)
I I I
Decarboxylative acylation of a-amino acids, in basic acetic anhydride (the Dakin-
West reaction), is a means by which the corresponding a-acetylaminoalkylmethylketones
may be prepared as shown in equation 109. This reaction has also been shown to occur
for non-amino acids such as phenylacetic acid and the reaction has recently heen
reviewed in detail324.
646 Jeffrey Hoyle
NH,CHCO,H
I
2s: b AcNHCHCOCH,
I
(109)
R R
Acid chlorides react with diazomethane to give the next homologous carboxylic acid,
after Wolfe rearrangement of the intermediate diazoketone (equation 1 10).This reaction
is known as the Arndt-Eistert synthesis. Other diazonium compounds also undergo a
similar reaction3” and the rearrangement step of this process has been reviewed
previo~sIy~~~.
Esters and lactones react with carbon tetrachloride, in the presence of triphenylphos-
phine under reflux, to give novel 2,2-dichlorovinyl ethers. These ethers may be hydro-
lysed to the corresponding a,a-dichloroketones as shown in equation 1 1 1 3 2 7 .
RC0,R’ -
CCI,
Ph,P
CCI,
II
RCOR’
HO+
3 RCCHCI,
0
11
Esters, thiolesters, lactones and anhydrides also react with ylids328-33’ and these
reactions have been reviewed recently332.In one such reaction, succinic anhydride was
reacted with (1 -ethoxycarbonylethylidene)triphenylphosphoraneto give an enol lactone
in 64% yield (equation 112)328-329. The product was then converted into a 2.2-
disubstituted-cyclopentan-1,3-dione; these compounds are important in the synthesis of
natural products such as sterols, tricothecenes and prostaglandins. In another reaction,
a thiolester was reacted with a ylid, containing a p-lactam moiety, to give a key penicillin
intermediate (equation 1 13)333.
In another example of the above methodology, aromatic acid chlorides were reacted
with ethoxycarbonylmethylenetriphenylphosphoraneto give acetylenic, chain extended
acid derivatives on flash vacuum pyrolysis (equation 1 14)330.331. The ester produced
may then be used as starting material and the reaction repeated to give conjugated
di- and triacetylenic esters330. At any stage in this process the ester grouping can be
removed to produce a terminal alkyne. This is a powerful method for preparing terminal
-
alkynes, and terminal alkynes with several other conjugated alkyne functionalities.
I . Ph,P=CHCO,Er FVP
RCoCl 2. FVP
b RCECC0,Et RC-CH (114)
11. Synthetic uses of carboxylic acids 647
B-Methoxyenones (which are useful in many synthetic applications) have been formed
by a two-carbon extension of acyl halides335.The acyl halide was added to a mixture
of freshly prepared 1-diazo-2-methoxyethane and triethylamine in ether. The diazo-
ketone produced was then converted into the enone by stirring with rhodium acetate
(equation 1 16).
CH,OCH,CHN, Rh AOAc),
RCOCI Et,N
N*
(116)
Acid chlorides react with 1,8-bis(trimethylsilyl)-2,6-octadiene,
at low temperature with
titanium tetrachloride catalysis, to yield 2,5-divinylcyclopentanolsand vinylcyclopentyl
ketones in a stereocontrolled manner (equation 117)336.If nitromethane is added as a
cosolvent, then only the cyclopentanols are produced337.If the acid chloride possesses
an wester group, then the ester and alcohol functionalities, in the product, react to give
spirolactones.
TMS \
+
TMS
- + &kR
RCOCl
(117)
Acyl halides also react with copper(1) cyanide338and other ~ y a n i d e s , , ~ - ~
to~produce
l
-
acyl cyanides (equation 118). The reaction gives improved yields if performed under
phase-transfer conditions342or with ultrasonic irradiation343.
CN-
RCOCI RCOCN (118)
either aldehydes and ketones or with the other acid derivatives, radical- and carbene-
mediated cyclizations and miscellaneous reactions.
1. Alkylations
Carboxylic acid derivatives require strong bases in order to form a-anions, which may
then be readily alkylated. Acid derivatives with a second activating group attached in
the a-position are more readily alkylated, via the enolate anion which is easy to produce
with a wide variety of bases (equation 119). Alkylation may be performed with a wide
range of alkylating agents including alkyl sulphates4’ and palladium
complexes with triphenylphosphine (equation 120)346-349. Both dialkylation and 0-
alkylation (favoured by aprotic solvents such as DMSO) are possible side reactions as
is saponification if one of the activating groups is an ester. Alkylations of dianions may
be performed in which case the first alkyl group is introduced at the more acidic position.
Z Z Z
) -=
!+ )- RX )-X
2- Z’ Z‘
Carboxylic acid dianions may be readily alkylated at the more reactive, a-site to
produce a-alkylated acids (equation 121)350.35’.This reaction has been reviewed by
Petragnani and Y ~ n a s h i r o ~ The
~ ’ . reaction is commonly followed by decarboxylation
which in case of keto acids, yields a ketone. Thus, acetoacetate has been used as a source
of an acetone enolate ~ y n t h o n ~ ~ ’ .
XE0.S
Nc4-:;
""7CN
CN
4 z)+cN
Z
I . KSCN (123)
Z = C0,Et NC Z
X,Y = halogens
Z = COzR
tions (PTC) using a quaternary ammonium catalyst, gives cyclopropanes in 73-91 '10
yield (equation 127)345*369.
The Sorensen method of amino acid synthesis uses a modification of the malonic ester
synthesis. In this modification an N-protected malonic ester is alkylated, hydrolysed
and decarboxylated to give an a-amino acid, as shown in equation 128.
CH,CONH -(
C0,Et
C0,Et
-1. base
2. R X
~.H*,A
NH,CHRCO,H (128)
X = halogen
Alkylation of 8-ketoesters with w-substituted alkyl halides is an efficient method for
the synthesis of cyclic products37'-3 7 4 . In one such sequence, the dianion of a [I-ketoester
reacted with 2-(2-bromoethyl)-1,3-dioxolane, the w-substituent in this case being a
masked aldehyde. Upon regeneration of the aldehyde functionality, a condensation
reaction occurred to give the cyclohexanone as shown in equation 13037'.
A thirteen-membered ring was formed by intramolecular alkylation, at the r-position.
of a /I-ketoester in 74% yield (equation 131)372.
A medium-sized ring has also been synthesized by a different route involving
alkylation of a [I-ketoester. In this case, ethyl cyclohexanone-2-carboxylatewas treated
with 1,4-diiodobutane in the presence of sodium hydride. The adduct. upon treatment
with radical initiators, gave a 10-membered ring as the major product (equation 132)373.
Similar reactions have also been performed that produce 5-, 6-, 12-, 13-and 14-membered
rings375.A similar process with anionic ring expansion has also been reported374.
Carbon-carbon bond formation at the a-position of a lactone is an important reaction
which has been reviewed previously352.The ene-reaction has recently become very useful
in the stereocontrolled closure of five-membered rings and this has been used in
conjunction with lactone alkylation. In one such synthetic sequence, alkylation of a
lactone was one step in the construction of a molecule that would potentially undergo
11. Synthetic uses of carboxylic acids 65I
&C02R
Ihydrolysis
@? 0
C02Et
Q*Q- (133)
X = halogen
distance between the enolate and the controlling asymmetric centre increases227.Such
stereocontrol is caused by the conformational properties of the particular lactone being
alkylated.
Lactams may be alkylated at the a-position by reaction with a strong base, such as
LDA o r hexamethyldisilazide, followed by treatment with an alkyl halide. Baldwin and
coworkers have used this methodology in their synthesis of unnatural amino acids from
protected pyroglutamates (equation 134)378.The same reaction has been used for
El
I
R
El = electrophile
alkylating five- to nine-membered lac tarn^^'^. It is noteworthy that a-alkylated seven- to
nine-membered lactams are quite hard to cyclize directly and so ring closure followed
by a-alkylation is an important synthetic sequence. a,@-Dialkylationof lactams has also
been performed. In this reaction, good diastereoselectivity was obtained by reacting
bicyclic lactams, derived from (S)-valinol and levulinic acid. with a base followed by an
alkylating agent in two cycles3".
">"' -
H CHO OH
'. HH
- 0,c
Ph
2. HJOt
>=
Anhydrides may be condensed with aromatic aldehydes in the presence of the
corresponding carboxylate anion to give either an r,B-unsaturated acid o r a 11-hy-
droxyacid (equation 136). This is the Perkin reaction and dehydration gencrally occurs if
the anhydride has two a-hydrogen atoms. In some instances the 11-hydroxyacid de-
carboxylates under the reaction conditions to give an alkenc. An important variant of
the Perkin reaction is the heterocycle producing. Erlenmeyer azlactone synthesis; this
is covered in Section V.
Condensation between compounds of type ZCH,Z' (whcre Z and Z' are electron-
withdrawing groups and at least one of them is an acid derivative) and aldehydes or
11. Synthetic uses of carboxylic acids 653
ArCHO + (RCHCO),O
I
R’
- OH R
I
ArCH-CRC0,H
I
/R
ArCH=C
‘CO,H
ketones (usually without a-hydrogen atoms) is known as the Knoevenagel condensation
(equation 137). The reaction is rarely of synthetic utility with aliphatic aldehydes3’”. A
modification of the reaction using pyridine as solvent, under high pressure at 190”C,
>=<’
has allowed the preearation of n,p-unsaturated acids from malonic acid and aliphatic
R)(R’ +
Z
) base , R
(1 37)
0 z R’ z‘
aldehydes383. Decarboxylation of the initial product usually occurs under the react ion
conditions384 but this is not so in all cases3”. If the acid derivative being condensed is
of the form ZCHRZ’, then the initially produced alcohol may be isolated or water may
be subsequently eliminated after decarboxylation as exemplified in equation 138386
R H
X
Z C0,Me
+ -
RifR”
0
R
Z
HR
R”
(1 38)
Z = CO,R
The Knoevenagel condensation reaction has been used in tandem with hetero-
Diels-Alder reactions3”, ene-reactions (equation 139)3’4-38’-393and allylsilane cycliza-
tion and related imine cyclization to prepare a wide variety of hetero-
cyclic and carbocyclic compounds. In the ene reaction the trans cyclopentane is formed
diastereoselectively on treatment of the initial adduct with a Lewis
I
ZnBr, (139)
Z
Z
654 Jeffrey Hoyle
I
R'
Ito and coworkers have used Reformatsky methodology to stereoselectively prepare
key intermediates for l/hnethyIcarbapenem s y n t h e ~ i s ~ ~The
* ~ ~diastereoselectivity
'~. of
this reaction is dependant on the bulk of the C-4 oxazolidone ring substituents and the
temperature of reaction. Best results were obtained in boiling T H F with 4,4-dialkyl-
substitution.
Under Reformatsky conditions 2-chloromethyl-2-propenoates are inert and the corre-
sponding iodo compounds undergo Wurtz-type coupling. However, the corresponding
bromo compounds undergo Reformatsky-type, metal-induced carbonxarbon bond
formation with a wide range of electrophilic reagents. The preparation of a-methylene-
y-lactones using this methodology has been reviewed by Hoffman and Rabe403. The
same conditions may also be used to stereoselectively react with carbohydrate derived
ketone^^'^.^' 5.
A wide range of natural products, especially steroids and alkaloids, have been
synthesized by reactions of carbonyl compounds with alkyl 2-bromomethyl-2-propeno-
ates under the above-specified, modified Reformatsky conditions and these syntheses
have been reviewed recentlyJ2'.
In another variation of Reformatsky conditions, 3-dialkylamino esters and 3-benzyl-
oxycarbonylamino esters have been prepared by reaction of ethyl 2-bromoalkanoates
with I-dialkyamino- and 1-benzyloxycarbonylamino-1-(I-bentotriazoly1)alkanes in the
presence of zinc and Me,SiCI (equation 141)40".
Z = C02R
1 1. Synthetic uses of carboxylic acids 655
In a synthesis of the first lignan discovered in humans and animals, Kirk and
coworkersSZperformed a double Stobbe condensation by reacting diethyl succinate with
3-benzyloxybenzaldehyde in the presence of sodium ethoxide, followed by hydrolysis,
esterification and then repeating the reaction sequence once more (equation 143). The
resultant bis-(3'-benzyloxybenzylidene)-succinicacid was then further processed to give
the lignans.
1
I I. esterification
2, PhCH,OQfHO/ NaOEt
1 3 . hydrolysis
a-Anions of esters react with aldehydes or ketones to yield the same products as
are produced in the Reformatsky reaction and this reaction has been used for the
preparation of some non-proteinogenic amino acid^^'^.^''. Decarboxylation often, but
not always4", occurs to give an a,/?-unsaturated ester, if the product has an a-hydrogen
atom.
Aldehydes react with in situ generated ester a-anions, which contains a chiral
a-sulphoxide moiety, to give asymmetrically induced /?-hydroxyesters after desulphuriza-
tion (equation 144)412.
I 1. RCH,CYn
CHCozBu-t 2. CaCO,, ,
I nu
*SOR
0
0
II ,COR"
RCH,C-OCH=C DME (145)
\
R' R"
R
656 Jeffrey Hoyle
0-alkyllactic acid anions have been reacted with aldehydes to stereoselectively give
either the erythro or the threo diastereomer of the a-alkyl-a,/3-dihydroxy carboxylic acid,
after hydrolysis of the resultant ether4l5s4I6. The best yields were obtained when the
aldehyde was highly volatile and hence could be used in excess, and then easily removed
from the product by distillation.
/I-Ketoacids react with aldehydes to produce a carbon-carbon bond at the a-position
in buffer at pH 7 with concomitant loss of carbon dioxide to give B - h y d r o x y k e t o n e ~ ~ ' ~ .
In their approach to the synthesis of polyquinanes, Cook and coworkers have used
dimethyl /I-ketoglutarate to stereospecifically produce bicyclo compounds upon reaction
with 1,2-diones, and similar compounds, in buffers at ambient temperatures (equation
146I4lSA2 '.
C0,Me
R
R'
(146)
5+i,-ao
performed using caesium carbonate, starting with a cyclic enone to give a dicarbonyl
cis-decalin (equation 147)422.423.
(147)
CO~BU-t H
Z = C02R kz
z z
Lactones and a-anions formed on reaction of lactones with LDA react with aldehydes
or ketones. This reaction has been utilized in the synthesis of the highly oxygenated
side-chain of depresosterol (equation 149)254.
In addition, aryl aldehydes may be condensed with a-anions of benzyl substituted
lactones to give alcohols. These products are readily cyclized to give isolariciresinols
(lignans) upon reduction of the lactone ring (equation 150)425428.The use of this
methodology in the synthesis of lignans has been recently reviewed by Ward377.
1 I . Synthetic uses of carboxylic acids 657
HO
OH
“3;
( 149)
HO-
I.LDA
2. Ar’CHO HO
- H+
R
0 Ar‘
@?,’ CH,OH
CH,OH
A (150)
Ar’
Anions formcd by reaction of a-chloroesters with bases like sodium ethoxide rcact
with aldehydes and ketones to produce a,b-epoxyesters (glycidyl esters)42’. This reaction
is known as the Darzens condensation and is exemplified in equation 151. Dianions of
a-chloro acids undergo a similar reacti01-1~~’.
The product epoxy acid derivatives may
be readily converted into aldehydes by acid catalysed decarboxylation.
Chiral tin enolates, formed from amide-containing heterocycles such as 3-amino sub-
stituted butanoylthiazolidine-2-thiones,readily react with aldehydes to give diastereo-
selective products as shown in equation 152431. This reaction has been successfully
used for the synthesis of (+)thienamycin.
RCH2
1 S
1. Sn(OTf),
NR
2.R’CHO
A
(152)
R’ H R
658 Jeffrey Hoyle
/3-Keto-thiolester anions undergo Michael addition with conjugated enones. The pro-
ducts may be readily cyclized to give useful angularly substituted bicyclic compounds
PsEt
(equation 154)433. Under high pressure, malonate anions also undergo 1,4-addition in
a similar manner, even with sterically hindered cyclic enones434.43s
Rr
R = Me, Et R' = H, Me
(154)
As part of the synthesis of manicone and related compounds, phosphorus ylids
containing a-carboxylate groups have been reacted with aldehydes and ketones in up
to 90% yields, giving a$-unsaturated acids (equation 1 55)436.
2RCH,C02R' - base
R
I
RCH2COCHC02R' (1 56)
CH,C02R CHC02R
(157)
(,,,R
11. Synthetic uses of carboxylic acids 659
Mixed Claisen condensations are possible between two different esters but this method
is usually only of synthetic utility if one of the esters does not possess a-hydrogen atoms.
-
For example, formates allow the introduction of an a-formyl into an ester, equation 158.
RCHZCOZR’ + HCOZR”
base
RCHC02R’ (158)
I
CHO
Dieckmann condensations are most successful for five- to seven-membered
rings329*437. However, large rings may be closed using high dilutions. Dieckmann
condensation of unsymmetrical diesters has been performed using solid-phase supported
reagent hemi is try^^^*^^*. Dieckmann cyclization of a half-thiol diester occurred re-
gioselectively to give five-membered homo- and heterocyclic compounds, as shown in
equation 159437.
COSEt
i
X
LCO,Me
C0,Me
(159)
X EE CH,, S,NC0,Et
Amides with a-nitrile groups undergo self-condensation upon treatment with sodium
ethoxide to give a product with a rather surprising structure (equation 160)439,which
was further processed to produce pyridazine derivatives.
CN
Lithium ester enolates react with acid chlorides, at low temperatures in THF. to
give a-a~ylation~~’.The a-anions formed by the reaction of chiral amides with BuLi are
also readily acylated, in an asymmetric fashion by acid chlorides (equation 161)44’.
OCHzOCH3 OCH,OCH
1
05
J-&OCH,OCH, 1. R‘COCI
2. BuLi , - a O C H 2 0 C H 3 (161)
Carboxylic acid dianions, formed by reaction of LDA with a carboxylate salt, react
with esters or acid halides to give C-acylation at the more reactive site442.The product
is a P-ketoacid which may be readily decarboxylated to produce a ketone (equation 162).
If the acylating agent used is a formate then the initially formed a-formylcarboxylate
usually decarboxylates to give an aldehyde. This latter reaction is an alternative to the
reduction methods for preparing aldehydes discussed in section 1l.B.
Malonates are readily acylated to form methanetricarboxylic esters (which are useful
660 Jeffrey Hoyle
( - )-Methyl elenolate has been synthesized via a key step involving radicals generated
at the a-position of an ester functionality as shown in equation 16744".
Arnides with a-iodo substituents form a-radicals upon reaction with ethyl iodide
and n-butyltin radicals (formed by sun-lamp irradiation). These radicals will cyclize if
correctly oriented intramolecular double bonds are present. Using this methodology the
natural product trachelanthamidine has been prepared in good yield (equation 168)"".
z-lodo- and a-bromoesters are diastereoselectively cyclized using chromium acetate in
1 1. Synthetic uses of carboxylic acids 66 1
OMe
oYo2M
I
,*-CO,Me
(167)
CHO
n = 0,2,3
662 Jeffrey Hoyle
In further studies, a-(n-alkyl radical)-P-stannyl-cyclic-B-ketoesterswere cyclized to
form 10-membered rings as shown in equation 17145-56. No reduction of the halide
to the alkane was evident in this case.
SnBu,
- SnBu,
Esters containing two conjugated double bonds, starting at the y-position have been
converted into tricyclic ketones, such as hirsutene, by initial formation of a n a-
diazoketone followed by carbene-mediated cyclization as shown in equation 172457.
Other ketone functionalities present in the molecule are unaffected and thus diketones
have also been prepared in this way458. In earlier work, Vandewalle and coworkers
have constructed a novel tricyclic-B-ketoester, via an a-diazo-p-ketoester as shown in
equation 173, which was subsequently transformed stereoselectively, with a range of
nucleophiles and electrophiles, into other cis-bicycl0[3.3.0]octanes~~~.
q C 0 2 M e A
Cu(acac), , 6'
5. Other
Several other ways of forming new C-C bonds at the a-position of an acid derivative
are discussed in this section.
Oxidative coupling of acid derivatives of the type ZCH,Z, such as ketoesters, occurs
upon reaction with iodine, silver oxide and other reagents. This reaction has been
successfully employed in the synthesis of carbocyclic rings (equation 174)460. Similarly
dianions of several acids have been oxidatively self-coupled or c r o s s - ~ o u p l e ld. ~ ~
1 1. Synthetic uses of carboxylic acids 663
C,O,Me
C0,Pr-i
RO
(178)
C02R'
C0,R'
/I-Lactams may be formed from cr-halo substituted acetamides by two electrochemical
reduction methods202. These involve C-C bond formation at the a-position, by
nucleophilic substitution of the halogen by the generated anion. This reaction joins C(3)
to C(4) in the product lactam. The reaction gives high yields and proceeds in the presence
of many groups that may be required to further elucidate natural product, /I-lactam
structures.
Intramolecular nucleophilic substitution of a chlorine atom in a a-chloro amide, by
a ketone enolate, causes cyclization and this has been used in the synthesis of some
alkaloid ring systems (equation 180)472.The product of this reaction is a key intermediate
for the synthesis of Strychnos, Aspidosperma, Schizozygane and Ehurnamine alkaloids.
1 I . Synthetic uses of carboxylic acids 665
OCH,Ph
R = SiMe,tBu
As part of a recent synthesis of the potent insecticide deltamethrin, a y-alkoxy-
a$-unsaturated lactone has been converted into a bicyclic compound by C-C bond
I +
formation at both the a- and B-positions upon treatment with Me,CSPh, in DMF
at - 78°C (equation 182)474.
I
THF Bu,NF
666 Jeffrey Hoyle
Finally, cyclic 1,3-diesters and diamides, like Meldrum’s acid, may be condensed
with carbon disulphide, in the presence of triethylamine, to give a bisalkythioylidene
derivative, after alkylation, as shown in equation 184476.
employed the adduct cyclized to give a furanose ring, and then ketolizes and spontan-
eously lactonizes to give 25% yield of the required product. This reaction is, un-
fortunately, not of general synthetic utility-vitamin C does not give adducts with
unsaturated acids, esters or acyl halides under these conditions.
r,/?-Unsaturated esters react with a wide range of carbanionic species to give C-C
bond formation at their /?-positions. Thus lithium ester enolates have been added to
ethyl 2-cyano-2-alkanoates to give glutarates in high yield (equation 186)482484.
Homologation to higher 2-alkenoates has been performed by reaction of Grignard
11. Synthetic uses of carboxylic acids 667
CHMe Me
- C0,Et (188)
OHC-
C02Et
Me0,C'
R* = chiral group
C02Me
- SC€
SCH,CHO
base ,
-===+
CO, Me
Me0,C
668 Jeffrey Hoyle
Michael-induced ring-closure reactions have been performed using a$-unsaturated
esters as the Michael acceptors. These reactions involve conjugated nucleophilic addition
to the acceptor followed by ring closure of the resulting enolate by displacement
of a leaving group. MIRC reactions have been classified as type I and type 11. In type
I MIRC reactions the Michael acceptor and the leaving group are in one molecule and
the nucleophile is introduced. In type I1 reactions the nucleophile and the leaving group
are in the same molecule and the acceptor is a separate entity.
Type I1 MIRC reactions, with acid derivatives, have especially been used for the
formation of cyclopropanes (equation 191)491494. O n the other hand, type I reactions
have usually been used for larger rings (equation 192)495-50'.
R' R
NHCH,Ph
+ PhCH'NSiMe, (192)
CH,CO,Et
In addition, multiple Michael-initiated ring closures have also been used effectivelv.
Y
6 Tw,
example, the carbon skeleton of diospynol has been prepared by reaction of a substituted
benzylic anion with methyl acrylate (equation 194).
H 0o ~ c o ' M e Pb(OAc),,
SnBu,
(193)
a$-Unsaturated lactones also undergo facile Michael reactions with carbanions to
give synthetically useful products. In one such reaction, trans-3,4-dibenzyl-substituted
butyrolactones have been synthesized by tandem conjugate addition of anions of
aryldiphenylmethane to butenolide, followed by anionic trapping with a benzyl bromide
(equation 19S)'06. In another reaction of this type, Michael addition of lithium di-
methylcuprates to 10- to 13-membered-a,/?-unsaturated macrolides has occurred in a
stereocontrolled fashion when methyl substituents are present adjacent to the ring
oxygen atom (equation 196)'".
a$-Unsaturated amides have been relatively rarely used as Michael acceptors and
only a few reports are available in the recently published literature480. Organolithium
compounds have been reacted with unsaturated N-phenylamides to give cleanly 1.4-
addition productsso7. Stereocontrolled addition of dialkylorganocuprates to unsaturated
lactams has been achieved by the presence of an exocyclic chiral centreso8.
11. Synthetic uses of carboxylic acids 669
C0,Me
I . LDA
Me&2Me Me 2. I f 0 2 M e ’ Me
YH OH OH OH
I I I
Me Me
Q G7 0 0
I . R,CuM
2. H,O+ ' R/\/CoZH
organolithium reagents give mixtures of a$-unsaturated ketones and diols, via reaction
at the carbonyl group5",
Cyclopentenes with conjugated ester groups and correctly placed leaving groups
undergo S,2' substitution of the leaving group with a wide variety of organocuprates and
Grignard reagents in the presence of copper([) salts (equation 199)5L2*513. The stereo-
chemistry of the reaction may be controlled in some instances.
X
C0,Me R- +
0 I . NaH
R
&CO,Me 3. CIPqOEr),
2. R,CuLi ' ACHCO,Me (200)
1. n-BuLi, 2eq
2. R'CHO
-
n-BuLi
TsCl
b C H O + r-BuLi, Zeq
OAc
PhS
OAc
a-% - 3
pyridines to substituted indolo[3,3-a]quinolizidines has shown that there is a pre-
ponderance of cis C( 12b)H-C(2)H product for C(4)-monosubstituted precursors (equa-
tion 205). For C(5)-monosubstituted compounds a trans C( 12b)H-C(3)H product is
formed (equation 206) whilst for 4,5-disubstituted precursors both cis and trans products
may be formed depending upon the exact substitution pattern in the starting material.
0 N
H (205)
Me0,C
R
R
I . 2 LDA
/ \
O C 0 , H / \
R G C O z H
0
Condensations of polyenolates of unsaturated carboxylic acids have been used in
the synthesis of retinoic acids5”. Thus, ketones react with polyunsaturated acids to give
products with extended conjugation, upon dehydration (equation 209). Extended con-
jugated systems may also be formed by iodine-mediated oxidative coupling of diene- and
triene-diolates of unsaturated carboxylic esters526.Such a process has been used for the
synthesis of dicarboxylic acids as shown in equation 210.
0 1. LiNEt,
The same workers found that (2)-4-hexenolide, rather surprisingly, gave SN2 ring
opening to produce (Z)-4-alkenoic acids (equation 213). These products are very useful
in the synthetic perfume and flavour industries and in the synthesis of some natural
(214)
oxonium salts, to give C-C bond formation at a remote position. The product ester
possesses a terminal double bond and has three more carbon atoms than the starting
material (equation 214)532.A similar reaction occurs with a 4-hexenolide by attack of
the allylsilane on the cyclic double bond.
A. Lactones
Synthesis of polyfunctional compounds with controlled stereochemistry is one of the
fine arts of modern science and the synthesis of macrolides is probably the pinnacle of
these achievements.
Lactones exhibit many useful properties especially in the field of pharmaceutical
synthesis. They are a very prevalent structural feature in natural products and are key
intermediates in many synthetic sequences. Hence many lactones have been given names,
such as Corey lactone, reflecting the scientist who introduced the compound as a key
intermediate. Much interest and effort was exerted in the development of strategies for
the synthesis of these heterocycles and there have been many reviews concerning the
synthetic utility of lactones, for example of halo lac tone^^^^ and of the synthesis of target
lactones, such as macrolide antibiotic^'^^.
Lactones may be readily prepared from w-hydroxy or w-halo acids or related
compounds, by halolactonization of acids and by ring-opening lactonization of cyclopro-
panes, as discussed below.
acid group is often activated, because of the unfavourable entropic factors and possibili-
ties of polymerization. This may be done, for example, by preparation of the thioes-
ter254.539*540.Thus, the 2-thiopyridyl ester has been used to prepare the 12-membered
lactone in the macrolide (R)-lasiodiplodin, a fungal metabolite of Botrysdiplodiu
threbromue, in 49% yield (equation 215)54’ and the 14-membered lactone in erythro-
my~in~~’.
-
OMe 0 Me
AgClO,
Me0
U U
Activation of the hydroxyl group has also been used to facilitate lactonization, for
example by conversion into a t ~ s y l a t e This
~ ~ procedure
~ ~ ~ ~ ~has. been used for the key
lactonization step in the synthesis of the Japanese beetle pheromone, (R, Z)-( - )-5-( 1-
decenyl)-2-oxotetrahydrofuran (equation 216)542.In a similar process, p-toluenesulpho-
nic acid catalysed condensation of 1,5-dihydroxynaphthalenewith ethyl 2-oxocyclohexa-
necarboxylate gave a 1: 1 adduct which spontaneously lactonized, producing the tetra-
cyclic ravidomycin skeleton543.
OH
CH,(CH,),C=C--( CH,(CH,),C=C--
CH,CH,CO,H
For six-membered lactones and spirolactones, ring closure may be brought about
via the enol of a y-keto acid derivative with acid catalysis (equation 217)”‘ or using
triphenylphosphine (equation 218)545.
Ar&C02H Are 0
The w-hydroxyl group may also be formed in situ by reaction with zinc. This method
has been employed in the synthesis of the lactone ring in the tetracyclic ravidomycin
family of anti-tumor agents (equation 219)546. Other reductions of a ketoacid with
S e l e c t ~ i d e ~or~ ’b ~ r o h y d r i d e ’and
~ ~ of an acid-ester with sodium in ammonia (equation
220)54’.550 or borane (equation 221)550also yield useful lactones. I t should be noted
that in the reductions of the acid-esters, borane gave the product with opposite
regiochemistry to that obtained by the use of sodium in liquid ammonia.
Substituted 7-aryl-5-oxo-SH-pyrano[4,3-d]pyrimidineshave been successfully pre-
pared from anions of 6-methyl-5-pyrimidinecarboxylates by condensation with aromatic
aldehydes. The key lactone ring closure occurs by reaction of the in situ generated
alkoxide ion with the adjacent ester group, as shown in equation 22255’.
11. Synthetic uses of carboxylic acids 675
(219)
OAc 0 OAc OH
(221)
ArCHO
Me0 CH, ~
Me0
Ar
(222)
Me0
Alkoxide ions from the reaction of P-formyl esters with organometallic reagents also
gave lactonization. In this case, stereoselectivity is controlled by the coordinating effects
of the metal ions with the two carbonyl groups (equation 223)552.
0
CHO
676 Jeffrey Hoyle
M e O a C H 2CON;;Ph)2
H‘
*
<
(224)
The synthesis of nine-membered lactones from hydroxyacids (or their equivalent)
usually gives low yields. However, excellent yields were obtained with an allylic alcohol
with a more rigid carbon chain. The rigidity serves to reduce the unfavourable entropic
factors of the ring-closure process5”.
The above-described lactonizations often produce dilactones as side products, how-
ever these are sometimes the target molecules of a synthetic sequence. Yields ofdilactones
may be enhanced by activation of both the acid-derived group and the hydroxy group.
Such a reaction has been performed using a thioester with an internal silyl ether (equation
2 2 5 p ’.
II
XO(CH2),CCH2COSBu-f
0 - 0
(225)
C02H
I K CO
4
(CH2)14 (226)
I
Br
3. By halolactonization
Halolactonizations of carboxylic acids are highly regio- and stereoselective processes
that are extremely important in the synthesis of natural products and their key
intermediates. These reactions have recently been reviewed’”. Such reactions are
performed by treatment of unsaturated acids or carboxylate saltsS’’ with sources of
11. Synthetic uses of carboxylic acids 677
electrophilic halogens. These sources include bromine or iodine with thallium(1) carbo-
nate5", N - b r o m o ~ a c c h a r i nl , ~~~h l o r a m i n e - T ~an
~ ' ,iodine(1) perchlorate-collidine com-
plex563and a mixture of iodine, potassium iodide and potassium b i ~ a r b o n a t e ' ~ ~ . ~ ~ ~ . ~
The lactonization process may also be brought about by a source of electrophilic
selenium 5 6 6 .
Regiocontrol of the reaction often depends on the reaction conditions employed. 'Thus
bromolactonization of the unsaturated acid in equation 227, using bromine and
thallium(1) carbonate, gave the y-lactone, whilst use of NBS in DMF gave the p-lactone
excIusiveIy5"'.
/ KI I,
(229)
Lactonization of 2-phenylethynylnicotinic acid, catalysed by mercuric acetate, leads to
a mixture of two bicyclic pyridine derivatives with ring structures that are often found
in natural products (equation 230)570.The regioselectivity favoured the pyrano- over
678
QfO*" C E C P h - dPh
Jeffrey Hoyle
+ *: CHPh
the furano-product. With the 3-carbamoyl derivative, an equivalent reaction can be
performed which, in this case, gives only the five-membered lactam.
(230)
4. From cyclopropanes
Cyclopropanes with carboxyl substituents undergo electrocyclic ring opening followed
by cyclization to give lactones. This reaction sequence is important in the synthesis of
furan- (equation 23 1) and pyran-derivatives (equation 232)571*572. Ring opening occurs
at the most hindered site, thus controlling the regioselectivity of the reaction.
Vinylcyclopropanes with geminal diester groups also undergo ring opening followed
by lactonization to give y-butyrolactones in the presence of bis(trimethylsilyl)sulphate
(equation 233)573. Some stereocontrol is exhibited in the generation of the new, third
mc0zR
chiral centre. Acid catalysed reaction of equivalent trialkylsiloxy substituted compounds
produces a,fi-unsaturated lactones219.
(TMS)2SO~,
0 (233)
CO,R
B. Lactams
Lactams are extremely important sub-units in natural product syntheses and their
methods of formation are discussed below. In particular, p-lactams are important in
penicillin and cephalosporin chemistry and these functionalities have thus received much
attention; some of this work has been
Lactams may be formed by intramolecular reaction of w-(N-substituted) acids, by
reaction of activated acids with imines and by other methods, including the novel 'Zip
reaction'.
I I . Synthetic uses of carboxylic acids 679
/I-, y- and &amino esters may be cyclized to give lactams in excellent yields, by
intramolecular reaction575P57R . For example, /I-hydroxyamides, formed from tartaric
acid, have been cyclized to give / I - l a ~ t a m s ~ ~ ~ ~ ~ ~ ~ .
Hydroxylactams have been synthesized by reductive cyclization of aromatic nitro
compounds containing a /I-alkoxycarbonyl group. Reagents such as Pd/charcoal/hydra-
zine o r ammonium sulphide o r zinc with acetic acid may be used for this reduction
process (equation 234). However, if the nitro group is reduced to the amine, for example
with Pd/charcoal/cyclohexane, then no hydroxyl group remains in the product (equation
235)58’.
R
P C 0NO22 H
$200
PdjC
NH,NH,’
R I
OH
-QOo
PdjC
cyclohexane
H
The usual method for forming /I-lactams is by reaction of activated acid derivatives (or
acids previously treated in situ with an activating agent) with imines, as exemplified in
equation 2365s2P587.
I.Pr,N, 0
N* CI
I-
RU
I
R’-CO,H 2. U ’ A N Me
/R ’ D , R ‘ (236)
0
R
The reaction of activated azidoacetic acid derivatives with an imine, or a cyclic imine,
is also a common route, employed for the synthesis of a-azido-/I-lactams (Bose reaction)
which are key intermediates in the synthesis of /I-lactam-containing alkaloids and sugars
680 Jeffrey Hoyle
(equation 238)586. Stereocontrol of the reaction depends upon the reaction conditions
used.
Five-membered lactams have been synthesized from trans-3-hexendioic esters by reac-
tion with primary amines. Replacement of the amine with ethylenediamines has resulted
in the formation of bicyclic compounds with two lactam moieties (equation 239)588.
,(
CO,R
NH,CH,CH,NHR'+ 0%
0
CO,R
I
R'
These products may easily be reduced to cyclic amines of importance in natural product
synthesis.
A novel ring expansion reaction of lactams to larger lactams (the so-called Zip
reaction) has been developed5B9based on the reaction of an aminolactam with a strong
base followed by transamidation by reaction with the internal amide ion as exemplified in
equation 240.
-RNH-
--*
n
(CH,),
I
C=O
I
(240)
NH NH
@q H
Et,N , H~--CO,R
'OBz
Lactams have recently been prepared in a relatively simple process involving reaction
of a lactone with a primary amine. In one striking example, the lactams in the
spirodilactarn-containing alkaloid, shihunine, were formed by reaction of a dilactone
precursor with methylarnine. The alkaloid product was then formed by reductive
removal of the carbonyl groups (equation 242)590.
Finally, a y-hydroxyarnide has been cyclized to a lactam by activation of the hydroxyl
group and formation of the N-anion of the internal amide (equation 243)5'6,
11. Synthetic uses of carboxylic acids 681
C H R - -
0
1. BuLi
2.TsCl R, aoR
I
(243)
RC0,R"
682 Jeffrey Hoyle
R
11. Synthetic uses of carboxylic acids 683
Triazine and triazole moieties are present in many important pesticides, and may
readily be prepared from acid derivatives. Thus, alkylammonium salts of triazoles are
formed in good yields by the reaction of primary amines with dimethyl diazomalonates
(equation 250)595.Complex keto dihydro-1,2,3-benzotriazinesmay be obtained from
substituted anthranilic acids by the reaction sequence shown in equation 251596. The
products are useful in peptide synthesis since a-amino esters of these compounds
suppress racemizations to a large degree.
-
C0,R
R0,C
)=N2 + RNH, N (250)
RO,C
I
R
@O&CO,Me
1. LDA
----,
Meo2'x.
a0
OH
C0,Me
.ilt
C0,Me
R"
R)=*=-C02R PhKO, R'$ph + ',$L,CO,R
R" (257)
CO,R Ph Ph
R"
(158)
\
C02Me
OH
-NHz+ Q
c~xcozMe SH
PTC CI
0
LU
A. In Dlels-Alder Reactions
The Diels-Alder reaction is one of the cornerstones of modern organic synthesis.
Electron-withdrawing, e.g. carboxyl-derived, functional groups present in the diene
increase the rate of the cycloaddition and alter its regio- and diastereoselectivity. The
rate increase is observed if either an electron-rich dienophile is used, or if the electron-
withdrawing group is present in the dienophile and the diene is e l e ~ t r o n - r i c h ~Such
'~.
choices of diene/dienophile, especially with acid-derived groups, have enhanced the
synthetic usefulness of the Diels-Alder reaction. In addition, important target molecules
may be synthesized with specific acid-derived groups present in the required
locations for further synthetic operations. This important area of carboxylic acid
chemistry requires a brief discussion.
The presence of carbomethoxy groups alters the diastereoselectivity of a Diels-Alder
reaction. For example, 2-cycloalkenones usually give endo products with dienes, but if
a carbomethoxy group is present at C-2 then exo-addition is either predominant or
exclusive6'5-618. The regioselectivity is also affected by the presence of strong electron-
withdrawing groups like esters6".
N-Dienyl amides and lactams are extremely useful dienes in the Diels-Alder synthesis
of natural products619. Such usefulness has been extended by the N-alkylation of these
amido compounds with an olefinic group present in the alkylating compound. This then
gives a molecule which is able to perform intramolecular Diels-Alder reactions with the
stereocontrolled formation of bicyclic compounds in a single step as exemplified in
equation 2636'0. The inter- and intramolecular Diels-Alder chemistry of N-dienyl
amides and lactams has recently been reviewed by Smith619.
Chiral butenolides have also received attention in Diels-Alder reactions. Thus, these
good dienophilic lactones have been reacted with a wide range of dienes. The selectivity
of these cycloadditions has often been found to be kinetically controlled6' '. The reaction
of chiral 2(5H)-furanones, a butenolide, with cyclopentadiene has been used to generate
enantiomerically pure endo and exo adducts in very good yields (equation 264)622.
Finally, thiopyran rings, which are present in some natural products with important
pharmacological activity, may be easily synthesized by Diels-Alder reactions using acid
derivative^^'^. This reaction may be performed both regio- and stereospecifically by
11. Synthetic uses of carboxylic acids 687
endo exo
I
CHO
1. r-BuLi (267)
2.101
(ii) a regioselective synthesis of substituted anthraquinones which are then useful in the
preparation of natural products and dyes (equation 267)629.
Another ortho-directed reaction involving acid derivatives is the o-hydroxylation
which occurs on heating copper salts of aromatic acids in the presence of hydroxide
ions and o-amination in the presence of ammonia630.
C. As Transfer Reagents
A few carboxylic acid derivatives, such as phthalimide and succinimide, have been
used as transfer reagents for a whole range of electrophiles to nucleophilic centres in
many synthetic organic operations.
Thus halogen cations are effectively transferred from N-bromo- and N-chlorosuccini-
mide. These reagents have been much used for electrophilic halogenations of sulph-
oxides6” and at allylic positions6”, for example.
Transfer of sulphenyl sulphur-containing electrophilic species, to compounds with
active methylene or methine groups, is also an important use of acid-derived transfer
reagents. In this case phthalimides are most often the reagent of choice. Sulphenylation
by this method followed by oxidation and elimination of a sulphinic acid moiety is an
excellent synthetic route to unsaturated compounds.
It is also important to note that phthalimido anions have been used extensively in
the Gabriel synthesis of amines, from alkyl halides (equation 268)633 or from alco-
h01s634.635
RX + N
*- - RNH,
0
D. Resolution of Chiral Amines
Resolution of amines is a very important process in organic synthesis since often only
one enantiomer of a synthetically prepared racemic mixture of an amine exhibits the
sought after biological properties’.
11. Synthetic uses of carboxylic acids 689
Carboxylic acids have been used in more than a thousand reported cases for the
resolution of such racemic mixtures of amines. These have been reviewed by N e ~ m a n ~ ~ ~
and by Jacques and coworkers637.The usual method of resolution consists of using a
naturally occurring, optically active carboxylic acid to form a mixture of diastereomeric
ammonium salts which are then separated by crystallization. The optically pure amine
is then regenerated by basification. More recently, synthetic chiral acids, for example
+
(9-( )-2-methyl-2-phenylbutanedioicacid, and its enantiomer, have been used since
both enantiomers are usually available in contrast to most naturally occurring com-
pound~~~~.
VII. ACKNOWLEDGEMENTS
The author would like to express his appreciation to the library staffs at the Nova
Scotia Agricultural College and Dalhousie University for all their kind assistance. In
addition, I thank the students, and especially my chemistry colleagues of the Department
of Chemistry and Soil Science at NSAC. Lastly I would like to thank Carl and Robert
and especially my wife, Niki, for all their patience and understanding and for their
support and encouragement when I needed it most.
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5. D. J. Ager, Chem. SOC.Rev., 11, 493 (1982).
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by U. Pindur in the present volume.
14. S . Patai (Ed.), The Chemistry of Ketenes, Allenes and Related Compounds. Parts 1 and 2, Wiley,
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Patai), Wiley, Chichester, 1979, pp. 267-490.
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700 Jeffrey Hoyle
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